The Agricultural Health Study (AHS) is a long-term prospective study of potential health effects associated with pesticides and other agricultural exposures. The study is funded by the National Cancer Institute and the National Institute of Environmental Health Sciences, with collaboration from the US Environmental Protection Agency and the National Institute for Occupational Safety and Health. We are examining cancer incidence and other health endpoints in licensed pesticide applicators, spouses and children from North Carolina (NC) and Iowa (IA). Over a 3-year period (1993-7), we enrolled more than 57,000 licensed applicators, representing 82% of eligible private pesticide applicators (largely farmers) in IA and NC and 43% of commercial applicators from Iowa. About 40% of the private applicators also completed a more detailed take-home questionnaire covering farming practices and health. Nearly 32,000 spouses of farmer applicators enrolled and 2/3 also provided data on reproductive health, including information on all children under age 21 at time of enrollment. About 70% of participants completed the first five-year follow-up telephone interview (1999-2003) and the response rate was similar for the second follow-up interview (2005-2010). A third health follow-up involving multiple data collection approaches (mail, telephone, or internet) began in summer 2013 and is expected to be completed in 2014. In addition to updating farming history and lifestyle exposures, the primary focus is on identifying incident cases of respiratory, neurologic, and autoimmune diseases as well as other outcomes reflecting the older age of this cohort. The cohort is regularluy followed through linkage with population-based cancer registries in IA and NC and vital statistics, including state death records and the National Death Index. Buccal-cell samples for DNA were collected from participants at the time of the first follow-up iterview. Additionally, buccal samples are collected on an ongoing basis from participants who develop cancers and other conditions of interest to facilitate nested studies of gene-pesticide interactions. A dietary assessment (food frequency questionnaire) also was completed by participants during the first follow-up. In-depth pesticide expsoure assessment has been carried out for selected chemicals in targeted samples of the cohort. Results have been used to validate study questionnaires and inform exposure classification. Non-cancer outcomes of particular interest have included neurological diseases and symptoms (Parkinson's Disease, hearing loss, depression, neurobehavioral function, and suicide, ALS), respiratory and allergic outcomes (asthma, rhinitis, and chronic bronchitis), cardiovascular disease (heart attack, stroke), diabetes (gestational and adult onset), autoimmune diseases (rheumatoid arthritis, lupus, and Sjogren's syndrome), age-related macular degeneration, fatal injury, and adverse reproductive outcomes (infertility, fibroids and endometriosis. Through collaboration with Fred Gerr, University of IA, we studied neurobehavioral function in a subsest of 701 farmers using a panel of standardized tests. High pesticide exposure events were associated with adverse CNS function, but we saw no strong evidence of association between organophosphate insecticide use and adverse CNS or PNS function. In the Growth and Puberty (GAP) Study, a pilot study to assess the feasibility of measuring early puberty markers (hormone levels in urine and saliva, height velocity, Tanner staging), we enrolled and followed 60 children. The Genes and Age Related Macular Degeneration (GENARM) study obtained medical records, opthamalogical photographs, and saliva as a source of DNA for individuals who reported incident macular degeneration at one of the followup interviews. Data analysis continues for the Farming and Movement Evaluation (FAME) study while new cases of Parkinson's disease continue to be captured (see report by F Kamel). Data follection for an in-depth study of respiratory diseases (The Lung Health Study)is nearing completion (see report by S London). The AHS cohort continues to participate in large data pooling prjects through the NCI-sponsored Cohort Consortium. In addition, the Agricultural Health Study is one of the founding members of the Agricultural cohort consortium (AGRICOH) and we hope to use this collaboration to enhance our ability to assess rare exposures and outcomes. Our work this past year included collaboration on NCI-led studies of specific cancers potentially related to pesticide use. In an updated analysis, methyl bromide was not associated with prostate cancer risk. Several gene pathways and gene-pesticide interactions were associated with prostate cancer risk, and some pesticides were more strongly associated with more agressive prostate disease. We continue to explore self-reported respiratory diseases and symptoms. A recent report of inverse associations between asthma exacerbation (among those with active disease) and several herbicides and agricultural activities is consistent with the possibility that individuals prone to asthma exacerbation may avoid exposures that trigger symptoms. We previously reported that pesticide applicators who used specific organochlorine and organophosphate insecticides were at increased risk for Type 2 diabetes. A paper currently under review explores diabetes risk among farmer's wives who reported ever mixing or applying pesticides. Similarly, we replicated previous findings of association of specific organochlorine insecticides and other chemicals with risk for hypothyroid disease among spouses in a new analysis of licensed pesticide applicators. We found increased odds of hypothryoidism associated with ever use of six herbicides and eight insecticides, including the organochlorine compounds chlordane, DDT, heptachlor, lindane and toxaphene. Exposure-response relationships were seen for the herbicides alachlor and 2,4-D and the insecticides aldrin, chlordane, DDT, lindane, and parathion. Results were similar to our earlier findings for spiuses, but consistent with their greater use of chemicals, more chemicals were found to be associated with thyroid disease risk.